Faculty Bibliography

The neonatal lupus syndrome is the most common cause of isolated congenital heart block. There is, at present, little information about the putative role of anti-SS-A/Ro SS-B/La antibodies in the pathogenesis of congenital heart block in the neonatal lupus syndrome. Using an in vitro experimental model, the present study was designed to test the hypothesis that IgG antibodies in the sera of anti-SS-A/Ro SS-B/La-positive mothers of infants with isolated congenital heart block bind to and affect the transmembrane action potential of rabbit cardiac tissue. The results demonstrate a preferential inhibition of membrane repolarization (ADP-50 and ADP-90) and staining of cardiac cells within the neonatal, in contrast to the adult, rabbit heart by sera and IgG-enriched fractions from anti-SS-A/Ro SS-B/La-positive individuals. The results of the electrophysiologic studies demonstrate a pathophysiologic role for the IgG fraction of anti-SS-A/Ro SS-B/La-positive maternal sera in inhibiting neonatal rabbit cardiac repolarization. It is possible that antibodies to similar determinants expressed on the cell membrane of cardiac-conducting cells also may play a pathophysiologic role in the development of idiopathic congenital heart block in humans

The physicochemical properties of apparently acid-labile IFN-alpha from patients with SLE have been studied. The antigenicity, apparent molecular size, and isoelectric point of SLE IFN-alpha are indistinguishable from those of conventional, previously characterized, acid-stable subspecies of IFN-alpha. However, after partial purification by anion-exchange chromatography, SLE IFN-alpha no longer exhibits acid lability, suggesting that other plasma factor(s) are responsible for the acid lability of SLE IFN-alpha. Addition of SLE plasma, but not normal plasma, to conventional acid-stable IFN-alpha renders the exogenous IFN-alpha acid labile. Preliminary results demonstrate that an acid-dependent IFN-inactivating activity can be partially purified from SLE plasma by anion-exchange chromatography

The iC3b receptor (CR3) is required for neutrophil adhesive functions, including homotypic aggregation. Because stimuli that enhance neutrophil adhesion also induce up-regulation of surface CR3, it is widely held that these two responses are causally related. We have dissociated CR3 display (immunofluorescence) from CR3 function (aggregation). Neutrophils isolated at 4 degrees C and rewarmed to 37 degrees C up-regulated surface CR3 twofold, but did not aggregate. The kinetics of FMLP-induced CR3 up-regulation were discordant with those of aggregation. In the absence of extracellular divalent cations, CR3 expression increased twofold after exposure to FMLP, but neutrophils did not aggregate. FMLP elicited 3.5-fold more aggregation than the ionophore A23187, yet less than one-half as much CR3 up-regulation. 3 mM sodium salicylate inhibited aggregation 55 +/- 4%, but had no effect on CR3 up-regulation. Conversely, 1 mM tetracaine completely inhibited CR3 up-regulation, while significantly enhancing aggregation. Neutroplasts expressed CR3, but did not up-regulate the receptor; in contrast, FMLP induced CR3-dependent aggregation of neutroplasts. We conclude that, although constitutive surface CR3 is required for neutrophil aggregation, the up-regulation of CR3 is neither necessary nor sufficient to promote cell-cell adhesion

A retrospective literature review revealed that in 41% of cases of complete congenital heart block (CCHB) there was at least one other affected sibling, emphasizing the considerable risk of carrying a second affected fetus with CCHB. Therefore an aggressive approach was taken to prevent CCHB in a fetus with a high risk for the condition as defined by (1) presence of DR3 and high titers of antibodies to SSA(Ro) and SSB(La) in the mother (2) previous history of CCHB in a sibling. In a feasibility study, thrice weekly plasmapheresis was initiated in the 19th week of gestation to remove antibodies from the maternal circulation in advance of major placental transport to the developing fetus. Prednisone was also administered to decrease antibody synthesis. The concentration of total maternal IgG and antibodies to SSA(Ro) and SSB(La) were decreased by greater than 60% during the course of therapy. Planned delivery of a healthy baby was done at 36 weeks

Whether homotypic neutrophil aggregation depends on the quantitative increase of gp165/95 molecules (Mac 1, CR3) recruited to the cell surface during activation was studied using mAb of the CD11b group that recognize distinct epitopes encoded by the alpha-subunit of this glycoprotein. After the addition of antibody MN41, neutrophils did not aggregate in response to a chemoattractant, FMLP. Blockade of preexisting surface gp165/95 by mAb MN41, followed by removal of the excess antibody from the mixture, was used to show that the molecules of gp165/95 newly expressed in response to stimulation by a chemoattractant were incapable of effectively mediating the induced cell-cell interactions of aggregation. Flow cytometry studies confirmed that binding of unlabeled antibody MN41 did not block further increases in surface expression of gp165/95 after stimulation with FMLP. These data suggest that molecules of gp165/95 exhibit two functionally distinct forms, one, present on the surface of freshly isolated neutrophils, that becomes competent to mediate the aggregation response upon activation by a stimulus and a second form that can be translocated to the cell surface by the stimulus but is greatly diminished if not lacking in the ability to participate in that aggregation event

We measured levels of complement anaphylatoxin split products, C3a and C5a, in the circulation of patients with systemic lupus erythematosus (SLE). In 23 SLE patients who were followed serially, the mean C3a value was 179 ng/ml during stable disease and 550 ng/ml during a disease flare. In 10 patients, C3a levels predicted disease activity, with the C3a value rising from a mean of 183 ng/ml at a time of stable disease to a mean of 242 ng/ml 1-2 months prior to a clinical exacerbation of disease. The mean C3a level in 5 patients with acute dysfunction of the central nervous system (CNS) was 1,297 ng/ml, which is significantly higher than that observed in patients with active disease but without CNS involvement (P less than 0.01). C5a levels were also significantly elevated in 4 patients with acute CNS disease. Pathologic specimens from 2 patients who died during an acute lupus flare revealed neutrophils occluding the cerebral and intestinal vessels. Fluorescein angiography in a patient with CNS lupus revealed vasoocclusive retinopathy. In 5 of 7 SLE patients who were pregnant, C3a levels were elevated, with a group mean value of 310 ng/ml. There was a negative correlation (r = -0.59) between C3a and C3 levels in pregnant patients with SLE, and this finding is consistent with complement activation as the cause of decreasing C3 levels. We suggest that serial measurements of C3a can predict flares of disease in lupus patients and can demonstrate complement activation during pregnancy in women with SLE. In addition, release of C3a and C5a (mediators of inflammation) into the circulation may elicit vascular injury, particularly in patients with lupus cerebritis